Overweight is considered a very important problem in today's society, not only because of cosmetic considerations but also for medical reasons, especially when weight exceeds normal ranges to the point of obesity. Typically, dieting to reduce food intake, along with increased exercise, is used to reduce weight (or to prevent weight gain). Persistent and strict dieting is very difficult to maintain, however, and a number of drugs have been used in the past in attempts to suppress appetite and, consequently, food intake, and thus to make adherence to a dietary regime more tolerable. Amphetamine-type drugs have been used for this purpose for some time, but these drugs have dangerous side effects, present a significant addiction problem, are not always effective and are subject to tolerance development within a short period of time. More recently, naltrexone and other narcotic antagonists have been proposed for use as appetite suppressants. Nevertheless, there remains a serious need for yet other pharmacological means for weight control.
It is now well recognized that food intake and body weight vary during the estrous cycle in the rat. A consistent observation is that food intake and body weight decrease during the follicular phase of the estrous cycle when serum concentration of estradiol increases. In contrast, food intake and body weight increase during the luteal phase of the rat's estrous cycle when estradiol levels decrease and progesterone concentrations are elevated. Similarly, food intake and body weight increase after ovariectomy, a state of gonadal steroid deprivation, and during pregnancy and pseudopregnancy, when progesterone levels are increased. These observations indicate that endogenous estradiol is suppressory to food intake and the lack of estradiol is associated with enhanced food intake and body weight gain. It also would appear that the effects of estradiol on food intake are more transistory than the effects on body weight; thus, the actions of estrogen may be much more complex than simple appetite suppression. For representative literature in this area, see Tarttelin et al, Acta Endocr. 72: 551-568 (1973); Yoshinaga et al, Endocrinol. 85: 103-112 (1969); Landau et al, Horm. Behav. 7: 29-39 (1976); Wade and Zucker, J. Comp. Physiol. Psychol. 72: 328-336 (1970); Wade, Physiol Behav. 8: 523-534 (1972). It is interesting to note that while Tarttelin et al report potent effects of estradiol administration in ovariectomized rats, they note that estrogen treatment of intact females interrupted normal vaginal cycles but did not significantly affect food intake or body weight. Hervey et al, in J. Endocrinol. 33: 9-10 (1965), similarly noted loss of weight following estradiol administration to castrated rats of either sex, but little effect on the body weight of intact females similarly dosed with estradiol.
In ovariectomized rats, administration of estradiol, but not of progesterone or of testosterone, suppresses food intake and reduces body weight. Two lines of evidence indicate that the effects of estradiol on body weight are mediated by the central nervous system (CNS). First, the effects of administration of estradiol on reducing food intake and body weight occur in rats even after ovariectomy and hypophysectomy (removal of the pituitary gland) or adrenalectomy; Wade, Physiol. Behav. 8: 523-534 (1972). Secondly, implantation of crystalline estradiol benzoate into various hypothalamic regions reduced food intake in rats; Wade and Zucker, J. Comp. Physiol. Psychol. 72: 328-336 (1970). In that study, progesterone was found to be considerably less effective than estradiol, and testosterone was found to be ineffective. The effectiveness of hypothalamic implants of estradiol in suppressing food intake is not surprising since this brain region regulates food and water intake and neurons which concentrate this gonadal steroid have been described.
Nevertheless, the effects of estradiol on food intake (FI), water intake (WI) and a body weight (BWt) may be indicative of more complex effects not necessarily dependent on the CNS. As Tarttelin et al, in Acta Endocr. 72: 551-568 (1973), observe: "The initial effect on FI must be by action somewhere in the central nervous system but the long-term BWt and WI effects indicate that oestrogen might have some profound effect on body metabolism which need not be dependent on direct CNS participation, but rather may depend on other hormones with a peripheral action such as thyroid hormones, growth hormones or adrenal corticosteroids, although oestrogen could affect secretion of these hormones at the hypothalamic level."
The cyclic variation in food intake and body weight has been described for other species as well. The hamster, guinea pig, ewe, pigtailed monkey, baboon, rhesus monkey and human female show reduced food intake and body weight during the follicular (increasing estrogen) phase of their ovarian cycles and increase in these during the luteal (high progesterone/low estrogen activity) phase of their ovarian cycles. Additionally, systemic administration of estradiol to ovariectomized rhesus monkeys depresses food intake, while progesterone is ineffective. Thus, the suppressory effect of estradiol on food intake appears to be common to many mammalian species. See, for example, Morin et al, J. Comp. Physiol. Psychol. 92: 1-6 (1978); Czaja, Physiol. Behav. 14: 579-587 (1975); Rosenblatt et al, Physiol. Behav. 24: 447-449 (1980); Dalvit, Am. J. Clin. Nutr. 34: 1811-1815 (1981); Czaja et al, Hormone Behav. 6: 329-349 (1975); and Gilbert et al, S. Afr. J. Med. Sci. 21: 75-88 (1956).
There have been relatively few studies on steroid modulation of food intake and body weight in humans. Morten et al, in Am. j. Obstet. Gynecol. 65: 1182-1191 (1953), reported on a study of the premenstrual syndrome (PMS) in prison inmates. PMS is a late luteal phase condition. Among the women studied, 37% reported a craving for sweets and 23% indicated an increase in appetite associated with this state. Similarly, a craving for sweets was a frequently reported PMS phenomenon in 45 women studied by Fortin et al, as noted by Smith et al. Psychosom. Med. 31: 281-287 (1969). In Smith et al's own study, a craving for sweets and compulsive eating were associated with "a more frequent depression" during the late luteal phase of the menstrual cycle.
In a more quantitative analysis of the role of the gonadal steroids in body weight regulation in human subjects, Dalvit, Am. J. Clin. Nutr. 34: 1811-1815 (1981), recently reported that the calorie intake of 8 women was significantly higher during the luteal (high progesterone) phase than during the follicular (increasing estrogen) phase of two consecutive menstrual cycles. Pliner et al studied 34 women and observed, in Physiol. Behav. 30: 663-666 (1983), that the decrease in food intake during the follicular phase was associated with weight loss and that the increase in food intake during the luteal phase was concurrent with weight gain. Thus, in women, endogenously released estradiol has a consistent, albeit subtle, suppressory effect on food intake and body weight.
The use of oral contraceptives, which contain progestins and semi-synthetic estrogens, has been variously reported to cause increase or decrease in weight; these effects have been neither confirmed nor refuted. Fluid retention has been noted in "pill" users and this may be associated with the reports of weight gain in women who use oral contraceptives. Thus, there is no consistent evidence for the effects of oral contraceptives on body weight in women.
At the present time, estrogens are generally administered to control symptoms of menopause; for postmenopausal osteoporosis, dysmenorrhea, menorrhagia, amenorrhea, atrophic vaginitis, ovarian dwarfism and post partum breast engorgement; in combination with progestins in oral contraceptives; in breast cancer; and in men in prostatic carcinoma. These uses are a reflection of the significant physiological and pharmacological actions of the estrogens, especially on the reproductive organs. Unfortunately, some significant toxic effects, including increased risk of thromboembolism, thrombophlebitis and endometrial carcinoma, are associated with the use of these hormones in therapy.
Recently, a chemical delivery system (CDS) has been devised which promises to deliver centrally acting drugs, such as the estrogens, to the brain in a sustained and site-specific manner. In accord with this system, the desired centrally-mediated hormonal effects of the estrogens can be achieved without the high concentrations throughout the body which are believed to be responsible for the significant toxic effects generally associated with use of these drugs. The estrogen-chemical delivery system is generally described in Bodor U.S. Pat. No. 4,479,932 issued to U. OF FLORIDA on Oct. 30, 1984, and more specifically in U. OF FLORIDA'S International Application No. PCT/US83/00725 (published under International Publication No. W083/03968), in Bodor U.S. Pat. No. 4,540,564 issued to U. OF FLORIDA on Sept. 10, 1985. Briefly, according to the estrogen-CDS system, the target estrogen is tethered to a reduced, blood-brain barrier penetrating lipoidal form of a dihydropyridine.revreaction.pyridinium salt type redox carrier. Oxidation of the dihydropyridine carrier moiety in vivo to the ionic pyridinium salt type estrogen/carrier entity prevents elimination thereof from the brain, while elimination from the general circulation is accelerated, and subsequent cleavage of the quaternary carrier/estrogen species results in sustained delivery of the estrogen in the brain and facile elimination of the carrier moiety. As stated in the aforementioned U.S. Pat. No. 4,479,932, the rationale for brain delivery of the steroid hormones, e.g. estradiol, at least in part derives from the fact that recent studies of histological mapping of hormone-sensitive and specific steroid binding cells in the brain have underscored the importance of steroid action in the brain on sexual behavior. Further details of the estrogen-chemical delivery system are given hereinbelow.